- The receptor protein tyrosine phosphatase sigma (PTPsigma) is a member of the mammalian leukocyte common antigen-related (LAR) family. Its expression is developmentally regulated in neuronal tissues. The Drosophila homolog of the mammalian LAR family of phosphatases (DLAR) controls axon guidance during Drosophila embryogenesis. We have demonstrated previously that mice deficient in PTPsigma have CNS and peripheral nervous system abnormalities. The sciatic nerve in the PTPsigma(-/-) mice demonstrates an increased number of small diameter fibers and slower nerve conduction velocities compared with PTPsigma(+/+) or PTPsigma(+/-) controls. To study whether peripheral nerve regeneration is affected by PTPsigma activity, we assessed nerve regeneration in the PTPsigma(-/-) mouse after three standard models of sciatic nerve injury. We report that after sciatic nerve crush injury, nerve regeneration was significantly faster in the PTPsigma(-/-) animals, as determined by histologic, electrophysiologic, and neuromuscular testing. After sciatic nerve transection with immediate microsurgical repair or allografting, PTPsigma(-/-) nerve fibers demonstrated errors in directional growth compared with controls. We propose that PTPsigma regulates the axonal regeneration rate and guidance of regenerating fibers.